The Autonomic Disorders PPG will continue its focus on the pathophysiology of orthostatic intolerance and neurogenic orthostatic hypotension and develop novel therapies in the treatment of autonomic failure. Several important innovations strengthen this competitive renewal. Project 1 will continue its focus on postural tachycardia syndrome (POTS) and neurogenic orthostatic hypotension (OH). Major emphasis will be placed on a clinical trial of a novel therapy (pyridostigmine) in POTS, a prospective study to identify predictors of bad outcome in POTS, and immunotherapy of a3 AChR autoantibody-positive and negative autoimmune autonomic neuropathy (AAN). Project 2 (Dr. Eduardo Benarroch) will continue the highly successful major aim of elucidating the structural basis for major clinical deficits in multiple system atrophy (MSA) and will extend the focus to dementia with Lewy bodies (DLB). In the renewal we will extend the findings to an important new area, the hypothalamus, an area that he is uniquely qualified to undertake. Project 3 (Dr. Michael Joyner) will become even more integrated with Project 1, focusing on the importance of blunted adrenergic vasoconstriction and exercise in POTS. Project 4 (Dr. Steven Vernino) is an important new project that focuses on the autoantibodies of AAN. This project interdigitates with Project 1 and will passively transfer immunoglobulin from both autoantibody positive and negative cases to mice to evaluate the development of experimental AAN. The Clinical, Administrative, and Physiology (CAP) Core is essential to coordinate and support these highly integrated studies. CAP Core is responsible for patient selection, patient screening and recruitment, performing baseline and follow-up autonomic studies, coordinating interactions among programs, and coordinating patient flow. The DATA Core provides the necessary computer programs and personnel to run the studies, a communal network to house a database and infrastructure to handle data reduction. PROJECT 1 P.I.: Phillip Low, MD Title: Autonomic Disorders Program Project Description (provided by applicant): In this competitive renewal, Project 1 will focus on elucidating the pathophysiology of POTS and autoimmune autonomic neuropathy (AAN) and will evaluate novel treatment strategies. Studies in this project will be driven by the Clinical, Administrative, and Physiology (CAP) Core and will intimately interdigitate with Projects 3 (Dr. Michael Joyner) on POTS, 4 (Dr. Steven Vernino) on AAN, and 2 (Dr. Eduardo Benarroch) on dementia with Lewy bodies (DLB).